"MD simulations indicate a possible role of parallel β-helices in seeded aggregation of poly-Gln"Martina Stork, Armin Giese, Hans A. Kretzschmar, and Paul Tavan
Biophys. J. 88 , 2442-2451 (2005).
The molecular structures of amyloid fibers characterizing neurodegenerative diseases such as Huntington or transmissible spongiform encephalopathies are unknown.Recently, x-ray diffraction patterns of poly-Gln fibers [Perutz et al. (2002) Proc. Natl. Acad. Sci. U.S.A. 99, 5591]and electron microscopy images of two-dimensional crystals formed from building blocks of prion rods [Wille et al. (2002) Proc. Natl. Acad. Sci. U.S.A. 99, 3563] have suggested that the corresponding amyloid fibers are generated by the aggregation
of parallel β-helices. To explore this intriguing concept,we study the stability of small β-helices in aqueous solution by molecular dynamics simulations. In particular, for the Huntington aggregation nucleus, which is thought to be formed of poly-Gln polymers, we show that three-coiled β-helices are unstable at the suggested circular geometries and stable at a triangular shape with 18 residues per coil. Moreover, we demonstrate that individually unstable two-coiled triangular poly-Gln β-helices become stabilized upon dimerization, suggesting that seeded aggregation of Huntington amyloids requires dimers of at least 36 Gln repeats (or monomers of about 54 Gln) for the formation of sufficiently stable aggregation nuclei. An analysis of our results and of
sequences occurring in native β-helices leads us to the proposal of a revised model for the PrPSc aggregation nucleus.
BMO authors (in alphabetic order):
Computation of structure, electrostatics, and conformational dynamics of PrPC induced by binding of Cu(II)
Structural Stability of the Cellular Prion Protein PrPC studied by MD-Simulations